Understanding how sensory stimuli are processed and lead to behavior is a fundamental question in neuroscience. Defining how local neural circuits process olfactory sensory information is an especially important?and still not well resolved?problem as structural aspects of the brain regions involved have been thoroughly studied and are evolutionarily ancient (and thus likely generalizable to other brain regions). What is not clear is how the known subtypes of inhibitory interneurons and their interconnections enable specific olfactory sensory processes such as odor learning and the dissociation of similar olfactory stimuli. Olfaction is also of great interest because the olfactory bulb is one of the first places that amyloid plaques develop in both humans with Alzheimer's disease (AD) and in rodent models of AD. While previous work has established a correlation between plaque development and olfactory dysfunction, very little is known about the cellular mechanism responsible for these behavioral changes. Within the olfactory bulb, amyloid plaques develop primarily in the granule cell layer, a region rich in a variety of GABAergic inhibitory interneuron subtypes. Our proposed work using whole cell patch clamp recording, combined with live multi-photon imaging of both neuronal morphology and plaque location, will determine whether nearby plaques in AD model mice selective alter the intrinsic physiology of the three major types of interneurons found in this layer: granule cells, Blanes cells and Golgi cells. Follow-up studies using focal application of exogenous Abeta (and control) peptides will determine if any changes in intrinsic physiology likely result directly from exposure to amyloid. In a second set of experiments, we will determine whether olfactory bulb slices containing amyloid plaques have impaired recurrent dendrodendritic inhibition and orthodromic (sensory-evoked) inhibition onto principal mitral and tufted cells. Together these experiments have the potential to define the cellular basis of the known olfactory impairments in AD model mice. Both the intrinsic and synaptic mechanisms revealed in this experimental study are likely to lead to novel and highly specific therapeutic approaches to control (and potentially reverse) the underlying dysfunction in AD model mice as well as revealing interneuron-specific functional signatures of AD progression that could be used diagnostically.